Human caliciviruses, classified in the Norovirus genus of the family Caliciviridae, are the most common cause of outbreaks of nonbacterial gastroenteritis in the U.S., being responsible for almost all outbreaks (>95%) of nonbacterial foodborne and waterborne gastroenteritis. These viruses are estimated to cause 23 million cases of gastroenteritis annually in the U.S., and are designated as class B biodefense pathogens because they (1) have an extremely low infectious dose, (2) can be transmitted by water, food, aerosols and by person-to-person spread, and (3) are highly stable in the environment. Currently, there are no countermeasures, except rehydration therapy to treat or prevent human calicivirus infections, and diagnosis is difficult. Large outbreaks of disease can cause economic problems and potentially overwhelm public health, military, and hospital capabilities. Once a facility is contaminated, eradication of infectious virus is difficult and expensive, and effective methods of evaluating decontamination remain unclear due in part to the inability to propagate the virus in cultured cells or animal models. This Program Project Aims to use multidisciplinary approaches to develop new rapid diagnostics and therapeutics to detect, combat and prevent human calicivirus infections. The Program Project will consist of 3 Projects and 3 Core facilities. Project 1 will develop new, broadly reactive diagnostic assays to detect human caliciviruses. Project 2 will develop methods to propagate viruses in cultured cells and express viral genes to assess infectivity and dissect mechanisms regulating replication. Project 3 will obtain high resolution information on the capsid structure, including identification of the carbohydrate binding site and discovery of capsid protein-genome interactions. Each project is dependent upon the experimental and intellectual contributions of the Core facilities: the Administration Core, Microscopy Core, and Protein Expression, Purification and Interaction Core. The success of this Program Project depends on the complementary expertise and integrated efforts of the individual investigators in the areas of diagnostic and environmental virology, carbohydrate biochemistry, molecular biology and virology, gastrointestinal biology, proteomics, and structural biology. Molecular information will be exploited to develop new methods to detect, treat and inactivate human caliciviruses.